The primary goal of this proposal is to develop opioid peptide aerosol-compatible formulations and an intranasal drug delivery system to deliver mu/delta opioid peptides to the central nervous system (CNS) in effective concentrations as the first step in developing a new class of safe and efficacious pain medications. Administration of traditional mu-opioid analgesics presents numerous problems, including gastrointestinal side effects, drug-drug interactions with other CNS depressants, and physical dependence. Opioid peptides which have dual mu/delta activity are a promising alternative because they possess effective analgesic properties but they tend to have greatly reduced, if any, of these serious side effects. They have been extensively investigated, but their administration has been limited to intracerebroventricular (ICV) or intrathecal (IT) injection, which has effectively prevented their clinical development despite thei considerable therapeutic promise. Opioid peptides administered via ICV or IT injection have also demonstrated an ability to enhance the analgesia of small molecule opioids (SMO), which could be exceptionally clinically useful in patients at risk for opioid toxicity, opiate addiction r who are tolerant of opioids. This approach will rapidly deliver opioid peptides including leu-enkephalin, biphalin, and beta-endorphin for analgesia directly into the CNS while greatly reduced side effect profiles, including tolerance and physical dependence. This approach has the potential to enable this class of opioid drugs which have high analgesic effect and little-to-n associated tolerance, addiction, or safety issues. Impel NeuroPharma has developed a novel aerosol based nasal device (termed a pressurized olfactory device, or POD) designed to bypass the blood-brain barrier (BBB) and deliver drugs directly to the brain via the olfactory connections in the upper nasal cavity (nose-to-brain delivery). Studies have shown that nose-to- brain delivery can increase CNS concentrations while lowering systemic concentrations with many types of drugs. The principal investigator Dr. John Hoekman and his team have significant experience in developing direct nose-to-brain opioid formulations for POD administration of drugs demonstrating significant improvements in brain:blood ratio as well as rate and extent of analgesia. Impel NeuroPharma Inc. will optimize and develop opioid peptide drug formulations using a non-invasive intranasal aerosol device for direct delivery to the CNS with greatly reduced systemic distribution.